The arachidonic acid (AA) cascade is the target of many pharmaceuticals that are therapies for various conditions such as cardiovascular and inflammatory diseases. For example, nonsteroidal anti-inflammatory drugs (NSAIDs) and selective cyclooxygenase-2 (COX-2) inhibitors block the conversion of AA to prostaglandins (PGs). Also, lipoxygenase (LOX) inhibitors, especially 5-LOX inhibitors, block the conversion of AA to leukotrienes (LTs). Several dual inhibitors that inhibit cyclooxygenase, e.g., COX-1, COX-2, or both COX isozymes, and 5-lipoxygenase are reported as potential agents for the treatment of inflammation (See Kirchner, T.; et al., Evaluation of the Antiinflammatory Activity of a Dual Cyclooxygenase-2 Selective/5-Lipoxygenase Inhibitor, RWJ 63556, in a Canine Model of Inflammation. J. Pharmacol. Exp. Ther. 1997, 282, 1094-1101), pain (See Praveen Rao, P. N.; et al., Synthesis and Structure-Activity Relationship Studies of 1,3-Diarylprop-2-yn-1-ones: Dual Inhibitors of Cyclooxygenases and Lipoxygenases. J. Med. Chem. 2006, 49, 1668-1683), and cancers (See (a) Barbey, S.; et al., Synthesis and Activity of a New Methoxytetrahydropyran Derivative as Dual Cyclooxygenase-2/5-Lipoxygenase Inhibitor. Bioorg. Med. Chem. Lett. 2002, 12, 779-782; and (b) Pommery, N.; et al., New COX-2/5-LOX Inhibitors: Apoptosis-Inducing Agents Potentially Useful in Prostate Cancer Chemotherapy. J. Med. Chem. 2004, 47, 6195-6206). However, there is a third major metabolic pathway involving cytochrome P450 metabolism in this same cascade, which metabolizes AA to epoxyeicosatrienoic acids (EETs). The soluble epoxide hydrolase (sEH) enzyme catalyzes the conversion of epoxyeicosatrienoic acids (EETs), which are cytochrome P450-mediated epoxides of arachidonic acid, into the corresponding dihydroxyeicosatrienoic acids (DHETs). EETs are known to exhibit vasodilatory, cardioprotective, anti-inflammatory, and anti-hyperalgesic effects while the DHETs are largely inactive (See (a) Spector, A. A.; Norris, A. W. Action of epoxyeicosatrienoic acids on cellular function. Am. J. Physiol. Cell Physiol. 2007, 292, C996-C1012; (b) Chaudhary, K. R.; et al., Inhibition of Soluble Epoxide Hydrolase by trans-4-[4-(3-adamantan-1-yl-ureido)-cyclohexyloxy]-benzoic acid Is Protective Against Ischemia-Reperfusion Injury. J. Cardiovasc. Pharmacol. 2010, 55, 67-73; (c) Li, N.; et al. Beneficial effects of soluble epoxide hydrolase inhibitors in myocardial infarction model: Insight gained using metabolomic approaches. J. Mol. Cell. Cardiol. 2009, 47, 835-845; (d) Node, K.; et al., Anti-inflammatory Properties of Cytochrome P450 Epoxygenase-Derived Eicosanoids. Science 1999, 285, 1276-1279; (e) Campbell, W. B. New role for epoxyeicosatrienoic acids as anti-inflammatory mediators. Trends Pharmacol. Sci. 2000, 21, 125-127; and (f) Inceoglu, B.; et al., Soluble epoxide hydrolase and epoxyeicosatrienoic acids modulate two distinct analgesic pathways. Proc. Natl. Acad. Sci. U.S.A. 2008, 105, 18901-18906).
NSAIDs target key enzymes involved in prostaglandin (PG) biosynthesis from arachidonic acid. However, morbidity and mortality due to NSAID-induced gastrointestinal (GI) toxicity are significant and frequent enough to limit the therapeutic use of this drug class. To mitigate this side effect caused primarily by COX-1 inhibition, COX-2 selective inhibitors, i.e., Coxibs, e.g., celecoxib (Celebrex) and rofecoxib (Vioxx), were designed to retain the beneficial anti-inflammatory and anti-hyperalgesic properties of NSAIDs but enhance GI tolerance. In spite of this design, at higher doses and long-term use, COX-2 selective inhibitors may lose selectivity and inhibit COX-1 in vivo, resulting in the aforementioned undesirable side effects. It has been demonstrated that drug combinations with low doses of NSAIDs and soluble epoxide hydrolase inhibitors (sEHIs) produce synergistic effects, with regard to anti-hyperalgesia and anti-inflammation, while decreasing side effects of Coxibs, e.g., cardiovascular toxicity.
Despite their benefits, there are practical challenges to developing combination therapies due to the cost and complexity of identifying optimal as well as safe dose regiments, dose ranges, and drug-drug interactions. Many of these challenges cannot be predicted a priori because two drugs that are safe when used independently of each other are not necessarily safe in combination. However, many of the challenges related to developing combination therapies, e.g., the prediction of pharmacodynamic and pharmacokinetic relationships, are substantially less complex if the polypharmacological action is derived from a single agent.
To prepare these single agents, there is a growing interest in a practice known as designed multiple ligands (DMLs) (See (a) Morphy, R.; et al., From magic bullets to designed multiple ligands. Drug Discovery Today 2004, 9, 641-651; (b) Morphy, R.; Rankovic, Z. Designed multiple ligands, an emerging drug discovery paradigm. J. Med. Chem. 2005, 48, 6523-6543; and (c) Morphy, R.; Rankovic, Z. The physicochemical challenges of designing multiple ligands. J. Med. Chem. 2006, 49, 4961-4970). DMLs are intended to enhance drug efficacy and optionally to improve drug safety relative to drugs that address only a single target by acting specifically on multiple targets, i.e., targeted polypharmacology. Also, DMLs have advantages over combination therapies because they circumvent the inherent problems associated with the formulation and administration of two or more agents. Furthermore, DMLs do not present safety issues that result from the differences in the pharmacodynamic and pharmacokinetic properties of individual agents. Therefore dual inhibition of COX-2 and sEH through a single molecule is likely to be more advantageous than co-administration of the drugs using combination therapy.
To date the Applicants are aware of only one example of a dual inhibitor related to sEH which was designed by GlaxoSmithKline, e.g., sEH/11β-HSD1 dual inhibitors (See International Patent Application No. PCT/US2009/051678, filed Jul. 24, 2009). As such, there is currently an unmet need in the field to which the present invention relates regarding the development of dual inhibitors that affect the P450 branch of the AA cascade. Surprisingly, the present invention meets this as well as other needs by providing a new class of DMLs, which are dual inhibitors of COX-2 and sEH.